Mouse metagenome strain:c57bl/6 | breed:Mus musculus
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ABSTRACT:
PROVIDER: PRJNA1305384 | ENA |
REPOSITORIES: ENA
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Project description:Post-hepatectomy liver failure (PHLF) remains a significant risk for patients undergoing partial hepatectomy (PHx). Reliable prognostic markers and treatments to enhance liver regeneration are lacking. Plasma nanoparticles, including lipoproteins, exosomes, and extracellular vesicles (EVs), can reflect systemic and tissue-wide proteostasis and stress, potentially aiding liver regeneration. Our study included nine patients with hepatocellular carcinoma (HCC) undergoing PHx. Patient plasma was collected before PHx as well as 1 and 5 days after and the EV-protein repertoire was analysed by quantitative mass spectrometry using a super-SILAC mix prepared from primary and cancer cell lines. This longitudinal proteomic analysis of the EVs circulating in the plasma of human patients undergoing PHx uncovers proteomic signatures associated with PHLF, which reflect dying hepatocytes and endothelial cells and were already present before PHx.
2025-08-11 | PXD059885 | Pride
Project description:The liver is the only organ in mammals, which fully regenerates after injury. To identify novel regulators of liver regeneration, we performed quantitative large-scale proteomics analysis of subcellular fractions from normal versus regenerating mouse liver. Proteins of the ubiquitin-proteasome pathway were rapidly regulated by partial hepatectomy, with the ubiquitin ligase Nedd4-1 being among the top hits. Knock-down of Nedd4-1 in hepatocytes in vivo through nanoparticle-mediated delivery of siRNA caused severe liver damage after partial hepatectomy and impaired regeneration, resulting in liver failure. Mechanistically, we demonstrate that Nedd4-1 is required for efficient activation of Erk1/2 signaling by receptor tyrosine kinases involved in liver regeneration through inhibition of receptor internalization, thus controlling a major pro-mitogenic and cytoprotective signaling pathway in the regenerating liver. These results highlight the power of large-scale proteomics to identify key players in liver regeneration and the importance of posttranslational regulation of growth factor signaling in this process.
2017-09-13 | PXD004108 | Pride
Project description:Background: Extended hepatectomies may result in post-hepatectomy liver failure, a condition with a high mortality. The main purpose of the present study was to investigate and compare the gene expression profiles in rats subjected to increasing size of partial hepatectomy. Methods: 40 Wistar rats were subjected to 30%, 70%, or 90% partial hepatectomy, sham operation or no operation. 24 hours following resection, liver tissue was harvested and genome-wide expression analysis was performed. Results: Cluster analysis revealed 2 main groupings, one containing the PH(90%) and one containing the remaining groups (baseline, sham, PH(30%) and PH(70%)). Categorization of specific affected molecular pathways in the PH(90%) group revealed a downregulation of cellular homeostatic functions degradation and biosynthesis, whereas proliferation, cell growth, and cellular stress and injury were upregulated in the PH(90%) group. After PH(90%), the main upregulated pathways were mTOR and ILK. The main activated upstream regulators were hepatocyte growth factor and transforming growth factor. Conclusion: With decreasing size of the future liver remnant, the liver tended to prioritize expression of genes involved in cell proliferation and differentiation at the expense of genes involved in metabolism and body homeostasis. This prioritizing may be an essential molecular explanation for post-hepatectomy liver failure.
2018-03-31 | GSE97429 | GEO
Project description:Surgical resection remains the gold standard for liver tumor treatment, yet the emergence of post-operative liver failure, known as the small for size syndrome (SFSS), poses a significant challenge. The activation of hypoxia sensors in a SFSS liver remnant initiated early angiogenesis, improving vascular architecture, safeguarding against liver failure and reducing mortality. The study aimed to elucidate vascular remodeling mechanisms in SFSS, its impact on hepatocyte function and subsequent liver failure. Mice underwent extended partial hepatectomy to induce SFSS, with a subset exposed to hypoxia immediately after surgery. Hypoxia bolstered post-hepatectomy survival rates. Early proliferation of liver sinusoidal cells coupled with recruitment of putative endothelial progenitor cells (EPC) via the VEGF/SDF-1α pathway, increased vascular density, improved lobular perfusion, and limited hemorrhagic events in the regenerating liver under hypoxia. Administration of G-CSF in hepatectomized mice mimicked the effects of hypoxia on vascular remodeling and EPC recruitment, but failed to rescue survival. Compared to normoxia, hypoxia favored hepatocyte function over proliferation, , promoting functional preservation in the regenerating remnant. Injection of AAV8-TBG-HNF4α virus for hepatocyte-specific overexpression of HNF4α, the master regulator of hepatocyte function, enforced functionality in proliferating hepatocytes but did not rescue survival. Only the combination of HNF4α overexpression and G-CSF treatment rescued survival afterSFSS-setting hepatectomy. In summary, SFSS arises from an imbalance and desynchronized interplay between functional regeneration and vascular restructuring. To enhance survival following SFSS-hepatectomy, a two-pronged strategy is essential, addressing the preservation of function in the proliferating parenchymal cells alongside the simultaneous mitigation of vascular harm.
2024-12-30 | GSE261425 | GEO
Project description:Arid1a is the subunit of SWI/SNF complex, which was reported to guide SWI/SNF to DNA. Here, we found that loss of Arid1a in the liver results in improved liver regeneration after partial hepatectomy.Genome-wide analysis showed that after hepatectomy,loss of Arid1a reduces the recruitment and activity of E2F4 on target promoters, resulting in expression programs that favor regeneration during injury. Correspondingly, these promoters showed increased H3k4me2 and H3k27ac marks, indicating de-repression of these E2f target genes. The post partial hepatectomy mice liver cells were fixed and isolated, analysis of genomic occupancy of E2f4,H3K4me2,H3K27ac in hepatocytes from Arid1a WT and Arid1a liver specific KO mice by ChIP-seq.
2016-03-30 | E-GEOD-76927 | biostudies-arrayexpress
Project description:Arid1a is the subunit of SWI/SNF complex, which was reported to guide SWI/SNF to DNA. Here, we found that loss of Arid1a in the liver results in improved liver regeneration after partial hepatectomy.Genome-wide analysis showed that after hepatectomy,loss of Arid1a reduces the recruitment and activity of E2F4 on target promoters, resulting in expression programs that favor regeneration during injury.RNAseq shows transcriptional profiling in WT and Arid1a LKO livers pre- and post-hepatectomy, which confirmed the E2F4 target genes and cell cycle genes were upregulated after hepatectomy. After partial hepatectomy, liver transcriptional profiling in WT and Arid1a liver specific KO mice were generated by RNA-seq analysis.
2016-03-30 | E-GEOD-76926 | biostudies-arrayexpress
Project description:Deletion of the RPS6 gene in mouse liver results in the inhibition of 40S ribosome biogenesis and the failure of hepatocytes to enter S-phase following partial hepatectomy. This microarray experiment was designed to assess the effects of RPS6 deletion on the expression of genes involved in liver regeneration following partial hepatectomy. Keywords: time course, liver
2009-05-01 | GSE13864 | GEO
Project description:Background and aims: Lethal liver failure is an important clinical issue. To overcome liver failure, we focused on liver regeneration mechanisms by activation of HSCs and KCs. It is known that the HSC-secreted Mac-2 binding protein glycan isomer (M2BPGi) has a function to activate Kupffer cells (KCs) in fibrotic liver. However, the importance and functional mechanism of liver regeneration by HSCs/M2BPGi/KCs axis in remnant liver after hepatectomy are still unknown. The aim of this study is to clarify whether the HSCs-derived M2BPGi can activate KCs in damaged-liver by not only fibrosis but also after hepatectomy and to elucidate the new molecular mechanism of liver regeneration by HSCs and KCs. Methods: We examined the effect of M2BPGi on human hepatocytes and KCs, and explored secretory factors from M2BPGi-activated KCs by proteomics approach. Further, the effect of Glucose-regulated protein 78 (GRP78) as one of the M2BPGi-related secreted proteins on liver regeneration was examined in in vitro analysis and mouse hepatectomy model. Results: Although M2BPGi had no hepatocyte promoting effect, M2BPGi promoted the production of GRP78 in KCs. The KCs-drived GRP78 promoted hepatocyte proliferation. GRP78 administration facilitated liver regeneration in 70% hepatectomy mice and increased the survival rate in lethal 90% hepatectomy mice with liver failure. Conclusion: The M2BPGi activated-KCs extract the GRP78 which facilitates liver regeneration via activation of the proliferation potency of hepatocytes. Moreover, GRP78 administration could improve the survival in the lethal mice model. Our data suggested that the new hepatotrophic factor GRP78 may be a promising therapeutic tool for lethal liver failure in the clinic.
2021-06-29 | GSE179005 | GEO
Project description:Arid1a is the subunit of SWI/SNF complex, which was reported to guide SWI/SNF to DNA. Here, we found that loss of Arid1a in the liver results in improved liver regeneration after partial hepatectomy.Genome-wide analysis showed that after hepatectomy,loss of Arid1a reduces the recruitment and activity of E2F4 on target promoters, resulting in expression programs that favor regeneration during injury.RNAseq shows transcriptional profiling in WT and Arid1a LKO livers pre- and post-hepatectomy, which confirmed the E2F4 target genes and cell cycle genes were upregulated after hepatectomy.
2016-03-30 | GSE76926 | GEO
Project description:MicroRNAs have been reported to control liver regeneration though the underlying mechanisms remain largely unclear. We used microarrays to examine microRNA profiles in the mouse liver at 48 hrs versus 0 hr post 70% partial hepatectomy.
2017-02-10 | GSE68451 | GEO